PROJECT SUMMARY It is well established that aging drives the impairment and degenerative processes of various organ systems within the body. In the heart, age-related changes are important risk factors for ischemic heart disease, which is the leading cause of morbidity and mortality in the United States. Recent studies have shown that circulating factors found in young blood can partially reverse age-related loss of cognitive function, restore muscle dysfunction, and improve strength and endurance exercise capacity. While much of the focus has been on the neurological field, a recent report identified a single factor in the blood of a two month-old mouse capable of reversing age-related cardiac hypertrophy. Interestingly, it is also clinically observed that pediatric patients are able to restore baseline cardiac function after injury faster than in the aged population. Research from our laboratory has demonstrated that systemic delivery of neonatal plasma into adult mice after ischemia-reperfusion (I/R) injury offers protection from scar formation, improves cardiac function, and promotes vascular remodeling. From these observations, we hypothesize that there exists ?pro-youthful? factors in neonatal plasma that offer a protective milieu and prevent irreversible myocardial damage. Thus, the overall goal of this proposal is to identify pathway(s)/factor(s) found in neonatal plasma that may be the main drivers in improving cardiac function after myocardial injury. We propose the following three aims: (1) determining a specific developmental period during which ?pro-youthful? factors are present in circulation and can mediate the protective effects observed, (2) examining the proteomic profiles of neonatal and adult mouse plasma to identify differentially expressed proteins and narrow down potential therapeutic candidates, and (3) determining gene expression changes of major cardiac cell types in response to I/R injury treated with neonatal plasma. The success of the proposed project could set the platform for therapeutic interventions to prevent the progression to heart failure after an acute myocardial infarction, which would greatly relieve the financial and health burden that it holds worldwide.